Advances in molecular genetics have made it possible to correct genetic diseases by introducing a non-defective gene into the afflicted host via somatic cells. The objective of this proposal is to test the hypothesis that skin is the organ most amenable to correcting many genetic disorders via somatic cell gene therapy, especially those characterized by deficiency of a plasma protein. We propose to take advantage of a unique animal model to examine the possibility of curing diseases by use of genetically modified skin. Murine hypotransferrinemia is a recessive disorder resulting from a splicing defect in the plasma transferrin gene; transferrin being the major iron binding protein in plasma. Homozygotes for this disorder have drastically reduced levels of transferrin, but demonstrate iron overload disease of the liver, heart and pancreas. These mutants exhibit severe anemia (a faithful replica of the rare human disease atransferrinemia) and at the same time manifest the complications of the more common disease, hemochromatosis. We propose to evaluate the ability of skin implants, expressing transferrin, to provide the absent plasma protein and thereby alleviate the clinical manifestations of severe hypotransferrinemia. Fibroblasts taken from homozygote mice will be transduced in vitro with a retrovirus plasmid containing the cDNA for either human or murine transferrin. The genetically modified fibroblasts will be implanted subdermally and the concentration of plasma transferrin as well as objective indices of the disease state assayed. In a second project we propose to evaluate the use of skin cells expressing a truncated version transferrin to manage iron overload diseases. A number of diseases exist in which iron overload can not be treated by conventional phlebotomies, thalassemia being the most notable. We hypothesize that a shortened transferrin molecule, a truncated transferrin, would act as a perfect iron chelator. It wound bind iron with high affinity, not be recognized by transferrin receptors, and would be excreted in the urine. We propose to graft a dermal matrix of genetically modified fibroblasts expressing a truncated transferrin gene beneath the skin of homozygote hypotransferrinemic mice and assay these transfected mice for reduction in parenchymal tissue iron. We feel that our previous studies on iron metabolism, the existence of the mutant mouse and the fact that the relevant genes are in hand, offers a unique opportunity to examine the use of skin cells in somatic cell gene therapy.